STRUCTURE/ACTIVITY RELATIONSHIPS OF C-TERMINAL NEUROPEPTIDE-Y PEPTIDE SEGMENTS AND ANALOGS COMPOSED OF SEQUENCE 1-4 LINKED TO 25-36

C-terminal analogues of neuropeptide Y have been synthesized. The influence of chain length, single-amino-acid substitutions and segment substitutions on receptor binding, biological activity and conformational properties has been investigated. Receptor binding and in vivo assays revealed biological activity already for amino acids 28 - 36 of neuropeptide Y [neuropeptide Y-(Ac-28 - 36)-peptide] which increased with increasing chain length. Replacement of Arg25 in neuropeptide Y-(Ac-25 - 36)-peptide had no influence on binding, whereas Arg33 and Arg35 cannot be replaced by lysine or ornithine without considerable decrease in receptor binding. The introduction of conformational constraints by the 2-aminoisobutyric acid residue (Aib) in position 30 and replacing the amino acids 28 - 32 by Ala-Aib-Ala-Aib-Ala decreased receptor binding. However, the corresponding Aib-Ala-Aib-Ala-Aib-substituted analogue and a more flexible analogue with Gly5 at position 28 - 32 exhibited considerable affinity for the receptor. All these substitutions led to a decrease in postsynaptic activity. Strong agonistic activities could be detected in a series of 10 discontinuous analogues, which are constructs of N-terminal parts linked via different spacer molecules to C-terminal segments. One of the most active molecules was neuropeptide Y amino acids 1 - 4 linked to amino acids 25 - 36 through aminohexanoic acid (Ahx) [neuropeptide Y-(1 - 4-Ahx-25 - 36)-peptide].